GENE-THERAPY FOR LUNG-CANCER - ENHANCEMENT OF TUMOR SUPPRESSION BY A COMBINATION OF SEQUENTIAL SYSTEMIC CISPLATIN AND ADENOVIRUS-MEDIATED P53 GENE-TRANSFER

A more effective gene therapy strategy for lung cancer using sequentia l cisplatin administration and adenovirus-mediated p53 gene transfer w as developed on the basis of our previous observation of enhanced expr ession of a reporter gene in malignant cells exposed to cisplatin befo re gene transfer, Transfer of the normal (wildtype) p53 gene into cisp latin-treated H1299 cells, in which p53 is homozygously deleted, resul ted in up to a 60% further inhibition of cell proliferation in vitro t han p53 transfer into untreated H1299 cells, The cisplatin plus p53 ge ne transfer strategy yielded significantly greater apoptosis and tumor growth suppression in an animal model of subcutaneous H1299 tumor nod ules than wildtype p53 gene transfer alone. The timing of cisplatin ad ministration and p53 gene transfer was shown to be critical: cisplatin administration simultaneous with or subsequent to p53 gene transfer w as less effective than cisplatin-first sequential treatment, Moreover, the in vivo inhibition of tumor growth was maintained by repeated cyc les of treatment, This gene therapy strategy has been incorporated int o a phase I clinical trial for the treatment of lung cancer and provid es a basis for the development of improved therapeutic protocols.